One of the molecules causally linked to cancer is the transcription factor STAT3. STAT3 is a member of the family of Signal Transducers and Activators of Transcription and is activated by specific tyrosine phosphorylation. The activity of STAT3 is normally controlled by a delicate balance of positive and negative effectors, and the objectives of this proposal are to understand mechanisms that govern this regulation. This information will provide knowledge needed to control its activity. As a signaling molecule, STAT3 can respond to signals generated in the cytoplasm or nucleus, but as a transcription factor it is essential for STAT3 to gain access to the nucleus. Specific Aim #1 is dedicated to STAT3 nuclear trafficking. Our premise is that regulation of STAT3 nuclear trafficking has a significant impact on its function, and elucidation of the mechanisms that regulate its cellular distribution will provide information valuable to block its function in cancer. In addition to nuclear localization, tyrosine phosphorylation of STAT3 is necessary for specific DNA binding and transcriptional induction. Specific Aim #2 is designed to evaluate the positive influence of breast tumor kinase, and the negative influence of the suppressor of cytokine signaling 3 (SOCS-3) on STAT3 function. Furthermore we will test the effect of STAT3 and SOCS-3 on cancer development with a murine model system. Results of these studies are expected to provide information fundamental to basic and translational research. Standard therapies for cancer include surgery, radiation, and chemotherapy, and newer strategies include specific inhibitors of hormone receptors (tamoxifen) or tyrosine kinases (Gleevec, Herceptin). Even with these interventions, cancer is one of the leading causes of death. It is clear there is a need to develop additional targeted therapies. Nuclear trafficking and inhibitors of tyrosine phosphorylation provide potential avenues for clinical intervention of STAT3-dependent neoplasia.